Send Orders of Reprints at
[email protected] Current Pharmaceutical Design, 2013, 19, 000-000
1
Microvascular Function/Dysfunction Downstream a Coronary Stenosis Giacinta Guarini1, Paola Giuseppina Capozza1, Alda Huqi1, Doralisa Morrone1, William M. Chilian2, Mario Marzilli1* 1
Cardiovascular Medicine Division, Cardio-Thoracic and Vascular Department, Cisanello Hospital, 56124 via Paradisa 2, University of Pisa-Italy; 2Integrative Medical Sciences Department, Northeastern Ohio Medical University, 44272 State Route 44, Rootstown Ohio- USA Abstract: For decades coronary macrovascular atherosclerosis has been considered the principal manifestation of coronary heart disease, with most of our effort dedicated to identifying and removal of coronary stenosis. However, growing body of literature indicates that coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function is of critical importance in understanding its role in disease, especially because these regulatory mechanisms vary substantially across species, vascular bed and due to comorbidities. Indeed, the most obvious consequence of coronary stenosis is that it may limit blood supply to the dependent myocardium to the point of causing ischaemia during exercise or even at rest. However, this flow limiting effect is not only due to the passive hydraulic effect of a narrowed conduit, but also to active responses in the coronary microcirculation triggered by the presence of an epicardial stenosis. To understand this problem it is important to review the inter-related mechanisms that regulate flow to the left ventricular wall and modulate transmural distribution of flow. These regulatory mechanisms operate hierarchically and are heterogeneously distributed along the coronary vascular tree. It is also important to discuss the effect of myocardial performance in modulating both blood flow demands and coronary resistance. Some of the interactions between coronary stenosis and microcirculation are transient, like those documented in acute coronary syndromes or during percutaneous interventions. However, microcirculatory remodeling may be triggered by a chronic coronary stenosis, leading to a sustained impairment of blood supply even after successful removal of the epicardial stenosis. A deeper understanding of these phenomena may explain paradoxical findings in patients undergoing coronary revascularization, particularly when functional tests are used in their assessment. These aspects are discussed in detail in this review.
Keywords: Coronary microcirculation, coronary stenosis, myocardial ischemia, endothelial dysfunction. INTRODUCTION Since the studies of Gould [1, 2], in every day clinical practice all the manifestations of ischemic heart disease (angina, acute myocardial infarction, sudden cardiac death and heart failure) have been considered the final effect of a focal narrowing of the epicardial coronary arteries. In this pathogenic hypothesis, epicardial stenosis by limiting flow in the distal vascular bed (coronary microcirculation) causes myocardial ischemia, whenever oxygen consumption exceeds blood flow availability. Although a number of experimental studies have supported these assumptions, many clinical observations have challenged the applicability of this conclusion derived from experimental models to patients. Evidence now exists that atherosclerosis causes more profound alterations in the regulation of myocardial perfusion, besides the hydraulic effects of epicardial obstructions. These alterations negatively impact the regulation of coronary vasomotor tone both in the large arteries and in the distal microcirculation [3]. Indeed, recent studies have documented that age, diabetes [4, 5], smoking habit, hypertension and other condition may interfere with the regulation of coronary blood flow at the microcirculatory level [6]. In the next session we will critically discuss the mechanisms involved in the regulation of coronary blood flow in normal condition, then we will provide readers with a more comprehensive and complex overview of the atherosclerotic coronary microcirculation. MECHANISMS OF CORONARY BLOOD FLOW REGULATION Several vasomotor control mechanisms contribute to the regulation of myocardial perfusion. The complex interplay of these *Address correspondence to this author at the Cardiovascular Medicine Division, Cardio Thoracic and Vascular Department, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; Tel: +39050996751; E-mail:
[email protected] 1381-6128/13 $58.00+.00
mechanisms must be finely tuned to assure, beat by beat, a perfect matching between coronary blood flow (oxygen and nutrients delivery) to cardiac metabolism (requests). Indeed, the mechanisms contributing to control of pressure and blood flow in the coronary circulation must serve two purposes. First, blood flow must be suited to the metabolic demands of the myocardium. That is, blood flow must be able to change in parallel with changes in metabolic demand. Secondly, capillary pressure must be regulated and maintained relatively constant despite changes in perfusion pressure so that efficient delivery of oxygen and nutrients is ensured without producing damage to exchange vessels. The regulation of vascular tone in the coronary microcirculation is particularly complex in all species investigated so far, in line with the critical role played [7]. Indeed, changes in vascular tone (i.e. resistance to flow) are essential for the adaptation of coronary blood flow to varying metabolic demands, with conduit coronary arteries contributing only about 7% to the overall coronary resistance [8] (Fig. 1). The majority of coronary vascular resistance is located at the coronary microcirculatory level, that is, in vessels with less than 150-200 microns in diameter; therefore, understanding the regulatory mechanisms that exercise control of the tone of these vessels is paramount to our understanding the control of myocardial perfusion both in normal and in pathological condition [9, 10]. 1. Metabolic Control Coronary blood flow is tightly coupled to myocardial oxygen consumption (MVO2), a process termed coronary metabolic dilation. Despite the seminal importance of metabolic dilation in titrating flow to changes in metabolism, it is incompletely understood how cardiac myocytes communicate a change in metabolic activity to the coronary vasculature [11]. In the traditional view, regulation of flow is thought as a negative feedback pathway, in which an imbalance between oxygen supply (delivered via flow) and oxygen
© 2013 Bentham Science Publishers
2 Current Pharmaceutical Design, 2013, Vol. 19, No. 00
Fig. (1). Distribution of resistance (% of the total) along the coronary vascular bed: epicardial coronary arteries (> 300 m), small arteries (300100m), arterioles (100-15 m), exchanging vessels (15-50 m), and veins (>50 m). Modified from Chilian, 1986 [9]
demands, results in the production of a metabolic dilator. The adenosine hypothesis is such a scheme, in which oxygen demands, in excess of supply would increase the production of adenosine through hydrolysis of ATP and subsequent dephosphorylation of ADP and AMP [12]. For several years, a prominent role in the metabolic regulation of coronary blood flow was attributed to adenosine, a purine nucleotide present in myocardial cells and in the extracellular space, with a very short half-life, that is rapidly taken up by circulating red cells, preventing systemic effects. Recent studies however, have proposed an alternative hypothesis (feed-forward theory) with a specific role for ROS and particularly for H2O2 [13] in the regulation of coronary vascular tone. The negative feedback hypothesis for metabolic regulation of coronary blood flow imply that after blood flow is increased to match oxygen supply with demand, there is no error signal to sustain the dilation. On the other hand, the H2O2 hypothesis centered on a different scheme, one in which the production of a metabolic dilator would be directly linked to myocardial oxygen consumption, working in a feed-forward manner. Moreover, H2O2 has all requirements of a metabolic dilator, being vasoactive [14, 15], has a short half-life (it is metabolized rapidly by catalase), it rapidly reacts with free thiol groups, and is freely permeable. Furthermore, the presence of catalase in the blood stream would confine its vasoactive effects to the producing organ system; this would prevent any spill-over of the dilation to non-metabolically active organ systems. Despite several unresolved issues general consensus is that metabolically active cardiac myocytes produce vasomotor substances, such as adenosine [16, 17], nitric oxide (NO) [18], prostacyclin [19], bradykinin [20], ROS [21] and H2O2 [22, 23] to promote vasodilation and sustain MVO2. Although, an increase in metabolic activity undoubtedly produces an increase in vasoactive metabolites at all levels of the coronary vasculature, metabolic control mechanisms appear to be most prominent in small coronary arterioles. When the effect of short coronary occlusions was studied in canine epicardial microvessels, only vessels less than 100 m in diameter dilated during the period of occlusion, whereas both large and small microvessels dilated during the reactive hyperemia [24]. 2. Coronary Autoregulation-Myogenic Control Coronary autoregulation refers to the intrinsic ability of the heart to maintain blood flow relatively constant despite marked changes in perfusion pressure [25]. During conditions of reduced perfusion pressure, vasodilation produced by autoregulatory adjustments contributes to maintenance of adequate blood flow to the myocardium [26]. Autoregulatory control is central to prevent
Guarini et al.
edema and microvascular damage by maintaining capillary hydrostatic pressure relatively constant despite large increases in coronary perfusion pressure. Reductions in perfusion pressure produce significant dilation of coronary arterioles smaller than 100 to 150 m in diameter [27] the magnitude of which is inversely proportional to vessel diameter. These observations indicate that autoregulatory mechanisms, as might be expected from pressure profiles of the coronary circulation, predominate in the microcirculation where they have the greatest impact on total coronary vascular resistance. In the coronary circulation, the most compelling evidence that a myogenic component contributes to autoregulation has come from studies of isolated coronary arterioles thus preventing interference and allowing the myogenic response to be controlled. Kuo et al. [28] demonstrated that porcine coronary arterioles 80 to 100 m in diameter exhibit myogenic responses to increases and decreases in transmural pressure. Active myogenic responses were evident in both subendocardial and subepicardial arterioles. Interestingly subepicardial arterioles, when compared to subendocardial arterioles, exhibited greater vasodilator responses at low pressures and augmented constriction at higher pressures. These differences in myogenicity may contribute to transmural differences in autoregulation; specifically, autoregulation in the subepicardium occurs at both lower and higher pressures than in the subendocardium [29]. The importance of these mechanisms becomes obvious when we consider that even minor changes of perfusion pressure at the capillary level results in major shifts in the amount of fluid that is exchanged between the intravascular and extravascular space. Although the myogenic reflex is regarded as the dominant mechanism in the so-called coronary auto-regulation, i.e., the maintenance of a steady flow despite marked variations in aortic pressure, it can actually be considered as the mechanism dedicated to the preservation of an adequate capillary pressure. Similar to other species, humans coronary microcirculation exhibits a myogenic response in subjects with or without coronary atherosclerosis [30,31]. Substantial investigations have been conducted to identify mediators and signaling cascades implicated in this control mechanism. One of the best supported hypotheses is that stretch activated cation channels on smooth muscle cells carry an inward current resulting in cell membrane depolarization during myogenic vasoconstriction [32]. Recent studies have identified specific channel of the TRP family on cerebral arteries of rats involved in stretch mediated-myogenic response [33, 34]. Several endogenous mediators have also been proposed to be involved in the myogenic constriction through regulation KCa channel activity, among them NO [35], PKC [36], mitogen-activated protein kinase (MAPK) signal transduction cascades [37, 38] and ROS[31]. For instance, it should be acknowledged that a specific mediator may be involved in the myogenic response in a vascular bed but not in another, that more than a pathway may be activated [39] and that species variability may also exist. Furthermore most of the studies were conducted only in animals. 3. Shear-Stress Similarly to pressure-activated control, changes in coronary blood flow velocity, and hence in vascular shear stress, also elicit immediate reactions of the coronary smooth muscle tone. A change in wall shear stress triggers the activation of complex signaling cascades on endothelial cells which ultimately induce the release of mediator(s) that by traversing the basement membrane, acts on the underlying smooth muscle cells to induce dilation. The resulted flow-induced dilation is called FMD. It has been suggested that FMD provide continuity in the dilator response throughout a vascular bed allowing communication between resistance arterioles and epicardial coronary artery. The metabolic response is more prominent at arteriolar level, where it induces vasodilation and a fall in vascular resistance with the aim to increases tissue perfusion. However, this increase in flow elicits FMD in the upstream conduit ves-
Microvascular Function/Dysfunction Downstream a Coronary Stenosis
sel, thus facilitating proper delivery of blood. Indeed, it has been documented that FMD is predominant in epicardial coronary arteries, where it causes dilatation when flow velocity increases and constriction when it tends to decrease, in order to keep a stable blood flow velocity and shear stress. In most vessels from different species and vascular bed NO has been documented to be involved in FMD [40-42]. Human coronary arterioles from subjects without CAD or other risk factors dilate to shear stress. This response is blocked by L-NAME, which is a potent inhibitor of NOS; conversely indomethacin, an inhibitor of cyclooxygenase, has no impact on FMD. This data suggest that in humans with no CAD, FMD is predominantly mediated by NO [43]. On the contrary, in patients with coronary atherosclerosis FMD is still an endothelium dependent mechanism, but is inhibited by blocking KCa channels suggesting a critical role for EDHF. Moreover, in this subset of patients EDHF seems to compensate for NO loss. Similarly, dilation to bradykinin is also mediated by EDHF, and relatively independent from NO [44]. In aged people, EDHF is the predominant dilators to maintain the same amount of dilation to bradykinin [45]. CAD, hypertension, diabetes and hypercholesterolemia are conditions associated to excess of ROS. As a result, NO bioavailability is reduced and NO-mediated vasodilation is impaired. In this contest EDHF plays a more prominent role in agonist-induced vasodilation. Thus in condition of enhanced oxidative stress where NO levels are reduced, EDHF can compensate for loss of NO-mediated vasodilation. Despite the fact that compensatory mediators and mechanisms are engaged in pathological condition to maintain homeostasis, alteration of one of these control mechanisms can exert a profound effect on the other ones, even when the signaling pathways of the latter are preserved. For instance, although atherosclerosis does not affect adenosine-mediated vasodilatation, it markedly affects the endothelial response to increase in shear stress, and thus reduces NO-mediated regulation of vasomotor tone. TRANSMURAL GRADIENTS IN FLOW Considerable data now exist which suggest that vascular reactivity differs between large and small coronary arterioles and that vasoactive reactions from similarly sized endocardial and epicardial arterioles also differ. Thus regional and positional differences must be considered when pressure/flow relationships and the control of resistance within the coronary microcirculation are investigated. These differences are often highlighted by the heterogeneous effects exerted on the coronary microcirculation during pathological conditions [46]. An example of this selectivity is the susceptibility of the left subendocardium to ischemia [47]. The transmural distribution of coronary blood flow across the left ventricular wall reflects the different impact of metabolic factors and mechanical properties of the left ventricle [48]. Indeed, moving from the surface of the heart toward the ventricular cavity, myocardial fibers operate under different hemodynamic conditions, and vessels are exposed to a varying degree of extravascular compression. This is true because within the left ventricular wall there is a gradient in contractile performance. Compared with the epicardial layers, the inner myocardial layers not only generate greater systolic tension, but also shorten more and faster. At the same time, systolic contraction impedes flow to the subendocardial layers during this phase of the cardiac cycle, to the point that the inner myocardial layers are perfused prevalently during diastole. The negative impact of systolic contraction on coronary flow becomes less and less prevalent toward the surface, to the point that subepicardial layers are perfused during all the phases of the cardiac cycle. These regional differences in contractile performance and perfusion call for additional mechanisms that help in regulating the transmural distribution of coronary blood flow [49], accordingly with the regional gradients in metabolism and performance.
Current Pharmaceutical Design, 2013, Vol. 19, No. 00
3
Given the regional and time-dependent variability of myocardial perfusion, an index called diastolic pressure time index (DPTI) has been proposed to better estimate subendocardial blood flow. Left ventricle oxygen requirements have been estimated using the systolic pressure time index (SPTI). The ratio DPTI/SPTI (i.e. the ratio of supply/demand) has been proposed to predict the adequacy of subendocardial perfusion. Consistently with previous observation, under normal conditions, the subendocardial layers receive about 20-30% more blood than the subepicardial layers; the ENDO/EPI flow ratio ranges from 1.1 to 1.3, confirming a moderate excess of flow to the inner layers, compensating for their greater metabolic request. Based on these assumptions, any increase of oxygen demand (SPTI) would be expected to cause subendocardial under-perfusion if not accompanied by a parallel rise in coronary perfusion index (DPTI). However, it should be kept in mind that myocardial contractile performance exerts a twofold effect on regional myocardial perfusion, because it is a major determinant of metabolic needs and a major determinant of vascular resistances. From previous experiments it appears that myocardial contractile performance can influence the ENDO/EPI flow ratio, independently from metabolic stimuli. In this sense, major changes in coronary flow in response to local changes in contractility have been reported under controlled conditions of steady perfusion pressure. Depression of myocardial contractility increases the ENDO/ EPI flow ratio, favoring subendocardial perfusion; conversely, enhancement of myocardial contractility lowers the ENDO/EPI flow ratio, limiting subendocardial perfusion. The wide fluctuations of coronary flow observed in these circumstances have been attributed primarily to changes in coronary extravascular resistances. When coronary perfusion is lowered progressively, maximal coronary vasodilation is reached earlier in the subendocardial vessels. Considering this and the fact that regional contractility has a more prominent effect on subendocardial flow, any prediction of transmural distribution of coronary blood flow should take into account the local contractile state [50]. Extreme changes in subendocardial intramural tension, like those observed in severe left ventricular hypertrophy or in dilated left ventricles with elevated end-diastolic pressure, may cause severe regional under-perfusion even in the absence of coronary stenosis [51-53]. ADDITIONAL MECHANISMS RELEVANT TO CORONARY BLOOD FLOW CONTROL Microvascular resistance can also be influenced by interactions between the vessel wall and circulating blood cells, particularly platelets. The clinical benefits of using antiplatelet agents in acute coronary syndrome have been widely demonstrated, leading to a Class II indication in clinical practice guidelines [54]. Their beneficial effects are commonly attributed to the reduction of thrombotic burden and the prevention of vasoconstriction at the culprit stenosis [55, 56]. However, separate assessment of the effects of abciximab, a powerful GP IIb/IIIa inhibitor, on the culprit stenosis and on coronary microcirculation has extended the benefits of this drug beyond the thrombus burden-reducing hypothesis. In this study conducted in patients with unstable angina and single-vessel coronary artery disease suitable for PTCA, platelet inhibition with abciximab was associated with an immediate improvement in myocardial blood flow as a result of a significant reduction in coronary microvascular resistance. Since the fall in coronary microvascular resistance following GP IIb/IIIa antagonist administration was similar under autoregulation and after maximal vasodilatation, a direct effect of platelet inhibition on coronary vasomotor tone could be ruled out [57]. Alternatively, in agreement with other reports, these observations suggest that platelet inhibition prevented microvascular obstruction, increasing the mass of perfused myocardium. In the quoted study, abciximab administration resulted in a further 30% reduction in microvascular resistances, in all study conditions, including high dose intracoronary adenosine administration. This mechanism might be part of a basic vascular reaction to local hem-
4 Current Pharmaceutical Design, 2013, Vol. 19, No. 00
orrhage or inflammation aimed to isolate and repair the damage. The authors of the study concluded that atherosclerotic obstruction has a relevant role in the pathogenesis of unstable angina, as all study patients had severe coronary stenosis, and its removal by stenting virtually abolished the pressure gradient, followed by complete relief from angina. However, the data supported also the role of an elevated microcirculatory vasoconstrictor tone in precipitating myocardial ischemia in unstable patients. The presence of a microvascular disorder in the post-stenotic vascular bed was also confirmed by the lack of normalization of coronary reserve after stenting, despite the absence of a significant pressure drop along the epicardial segment. Similarly, CFR and FFR were not correlated. These findings partially disagree with the concept that progressive stenosis decreases coronary reserve by dropping the distal bed pressure relatively more for smaller increases in flow suggesting once again the extremely important role the coronary microcirculation has in the regulation of myocardial perfusion [58]. EFFECT OF CORONARY STENOSIS ON CORONARY BLOOD FLOW The impact of coronary stenosis on coronary blood flow regulation was deeply investigated by Gould’s and colleagues in normal open-chest, anaesthetized dogs, in which one of the major coronary arteries (LAD or Cx) was instrumented with a screw vascular constrictor and a flow meter. In that seminal work a progressive reduction of coronary luminal diameter had no apparent effect on resting blood flow until the vessel became almost totally occluded by the constrictor [2, 58]. Only when coronary lumen reduction exceeded 80-85% of the original dimension, further reductions of the vessel diameter were associated with significant drops in resting coronary blood flow. Maximal blood flow was also initially unaffected by vessel constriction, whereas progressively decreased when vessel luminal reduction exceeded 75% of the original dimension. Further reduction in luminal dimensions caused a rapid fall in maximal blood flow (Fig. 2).
Fig. (2). Effect of lumen reduction (coronary stenosis) on resting and maximal blood flow in normal, anesthetized, open-chest dogs. Resting blood flow was unaffected by vessel constriction until coronary stenosis reached 80-85% of the vessel diameter, while maximal coronary blood flow started to decrease for stenosis more severe than 50%. Adapted from Gould, 1974 [2]
The capacity to maintain resting and maximal levels of coronary blood flow despite a progressive reduction in vessel diameter (until lumen reduction reached 75% of the original value) has been attributed to a compensatory mechanism in the distal coronary circulation. According to this hypothesis, in the area perfused by a stenotic vessel a parallel reduction of microvascular resistance would compensate the increased resistance to flow offered by the epicardial stenosis. As a consequence, ischaemia would develop
Guarini et al.
when microvascular dilator capability has been fully exhausted. This is not expected to occur until the stenosis is severe enough, exceeding about 75% diameter reduction. These observations have had an enormous impact on management of ischemic heart disease. Indeed, moving from those observations, the concept of “critical” coronary stenosis has been generated. The predictability of the hemodynamic impact of a coronary stenosis on myocardial perfusion (i.e. any coronary plaque determining an occlusion of the vessel more than 50% would determine myocardial ischemia) has completely changed our understanding of the ischemic heart disease. It has shifted diagnosis and treatment of ischemic heart disease from the ischemic myocardium towards atherosclerotic plaques. Obvious inconsistencies with these assumptions frequently emerge in daily cardiology practice, but unfortunately they go largely neglected. INFLUENCE OF CORONARY STENOSIS ON THE TRANSMURAL DISTRIBUTION OF MYOCARDIAL BLOOD FLOW From a physical standpoint, the primary effect of an arterial obstruction is the generation of a pressure gradient, as predicted by the Poiseuille equation. The peculiarity of this phenomenon is that the pressure gradient is proportional to flow, and thus any change in tissue perfusion is related to either an increase in upstream aortic pressure or to a fall in distal post-stenotic pressure. Although this basic hydraulic implication of arterial stenosis is frequently neglected, it has profound implications on flow regulation during ischemia. As mentioned above, the distribution of the coronary blood flow to the inner layers of the left ventricular wall can be predicted by the DPTI/SPTI ratio. The immediate effect of a coronary stenosis severe enough to generate some resistance to flow will be to generate a trans-stenotic pressure gradient. Being the proximal pressure always equal to the aortic pressure, the presence of a pressure gradient implies a post-stenotic pressure drop that is nonlinearly related to the severity of the stenosis and to the volume of flow. So, the more severe the stenosis and the greater the flow, the lower will be the post-stenotic pressure, that is the effective coronary perfusion pressure. Therefore the net effect of a severe coronary stenosis would be to induce subendocardial under-perfusion and possibly ischaemia [59]. MICROCIRCULATORY ADAPTATIONS TO CORONARY STENOSIS There is ample evidence suggesting that microvascular abnormalities develop in the myocardium subtended by a stenotic artery. Animal studies suggest that vascular remodeling occurs in coronary resistance vessels downstream from a severe coronary stenosis, resulting in a raise in “minimal” microvascular resistance. More recently, both structural and functional abnormalities have been reported by Sorop et al. [60] Arterioles extracted from post-stenotic myocardium demonstrated reduced myogenic responsiveness and increased sensitivity to endothelin-1. These functional modifications were associated with an increased passive stiffness of the vessels. These microcirculatory abnormalities may interfere with flow regulation (with independence of the hemodynamic effect of the stenosis) and may result in a state of sustained microvascular vasoconstriction and reduced vasodilator capability of the microcirculation. Microvascular dysfunction and abnormal vascular reactivity have been strongly implicated in precipitating myocardial ischemia/infarction in women in which epicardial coronary atherosclerosis is less prevalent than in male. Indeed, up to 50% of woman with ACS, without evidence of plaque rupture showed a typical ischemic pattern at CMR, while only 7% of women with plaque dysrupture at IVUS had an ischemic pattern on CMR [61]. Furthermore, a deep investigation of coronary vasomotor tone has revealed that 50-70%
Microvascular Function/Dysfunction Downstream a Coronary Stenosis
of patients with no obstructive CAD, admitted to emergency department for ACS, have provoked coronary artery spasm. Contrary to previous reports, there is no gender specificity for this phenomenon; coronary artery spasm can precipitate ACS in both sex [62]. 1. Dynamic Changes in Post-stenotic Microcirculation Gould et al. postulated that minimum microvascular resistance is independent of epicardial stenosis severity, and that microvascular vasodilation capability is preserved downstream from a coronary stenosis. Combined measurements of myocardial perfusion pressure and coronary blood flow allow estimation of proximal (transstenotic) and distal (microvascular) resistances. Sambuceti and colleagues used this technique to measure total (trans-stenotic + microvascular) and distal (microvascular) vascular resistances in the culprit vessel of patients with stable and unstable coronary syndromes. Measurements were performed under different conditions: at baseline, during maximal vasodilatation, and during pacinginduced myocardial ischaemia: measurements were performed before and after treatment of the stenosis with coronary angioplasty and stenting. Fig. (3) shows the results of those observations. Although under normal physiological conditions an increase in heart rate should be followed by progressive microvascular dilation and decrease in coronary resistances, in that study a paradoxical increase in coronary resistances was documented during pacing. This increase in resistance took place both at the level of the stenosis and the microcirculation, reaching its maximum value with the development of ischaemia [63, 64] (Fig. 3A, left panel). Conclusions were that, contrary to what predicted from animal studies, coronary resistances distal to a severe stenosis increase during tachycardia, contributing to the development of myocardial ischaemia and angina. This phenomenon was promptly abolished by the administration of intracoronary adenosine, was not prevented by alpha-receptor blockade, and disappeared immediately after angioplasty (Fig. 3B, right panel). Several mechanisms, either passive or active, might explain this paradoxical increase in stenotic and microvascular resistance during tachycardia. Passive mechanisms include vascular
Current Pharmaceutical Design, 2013, Vol. 19, No. 00
5
collapse caused by an increase in extravascular compression and reduction in diastolic time due to tachycardia [50]. This hypothesis contrasts, however, with the reduction of ST segment depression and the lack of increase in resistance of maximally dilated vascular bed during pacing. An alternative hypothesis would be that this reflects the activation of specific intrinsic control mechanisms of the coronary circulation. The aim of such mechanisms would be keeping coronary driving pressure within a critical range of values, on the one hand, high enough as to maintain perfusion through vessels with high opening pressure and, on the other, low enough to prevent capillary damage. In certain pathological scenarios, an active control of this kind could override metabolic control and exclude some vascular units for the sake of maintaining an adequate pressure to the perfused ones [65]. The reversal of pacing-induced ST segment depression by intracoronary adenosine administration strongly supports this hypothesis. In conclusion, in the ischemic myocardium an abnormal regulation of coronary vasomotor tone at the level of both large arteries and microcirculation takes place, impeding the utilization of potentially available blood flow. Such a phenomenon seems to be triggered, at least in part, by the drop in coronary pressure that takes place downstream from the stenosis. A similar study was conducted in patients with unstable angina undergoing PCI. Trans-stenotic and microvascular resistances were assessed in control conditions, at maximal vasodilatation, and during spontaneously occurring myocardial ischaemia. Here again, myocardial ischaemia was associated with a marked and dynamic increase in the resistances to flow at both the stenosis level and at the microcirculatory level, confirming the prominent role of microcirculatory vasomotor tone in the precipitation of myocardial ischemia in man [66]. The increase in microvascular resistance observed during ischaemia are associated with a marked perfusion heterogeneity within the ischemic myocardium, with flow values close to normal ones in some vascular units and close to zero in others [67]. Hence, downstream from a severe coronary stenosis, a phenomenon of de-recruitment of vascular units occurs, being proportional to the fall in driving pressure. Residual perfused vascular
Fig. (3). Changes in overall coronary resistance before (A) and after PTCA (B) in patients. In each column the specific contribution of coronary stenosis (light grey) and coronary microcirculation (grey) to the overall resistance is reported. Measurements were taken in 4 different conditions before and after revascularization: at baseline, during adenosine induced-hyperemia (AND), during stepwise increase in heart rate induced by atrial pacing (P1, P2, P max), and during maximal hyperemia and tachycardia (ADN+P max). On the opposite of what predicted by Gould’s, downstream from a severe coronary stenosis (A), maximal tachycardia induced increase in overall resistance as the effect of a combined increase in microvascular resistance and stenosis resistance to flow. Adenosine reversed such effect of tachycardia at both level (coronary microcirculation and epicardial stenosis). Stenosis removal immediately restored microvascular dilation in response to tachycardia (B). Adapted from Sambuceti 2001[60]
6 Current Pharmaceutical Design, 2013, Vol. 19, No. 00
units maintain a normal vasomotor tone, thus explaining the paradoxical persistence of coronary vasodilator reserve. 2. Stenosis Removal and Microvascular Function It might be expected that stenosis removal by PCI would abolish perfusion abnormalities, restore a normal microvascular behavior, and normalize coronary blood flow reserve. However, although successful PCI consistently abolishes paradoxical vasoconstriction in the post-stenotic vessels and expands the perfused myocardial volume, these effects are not associated with the normalization of minimal microvascular resistance and the recovery of coronary blood flow reserve [68-70]. As a matter of fact, both minimal microvascular resistances and coronary flow reserve remain abnormal in a large fraction of patients after stenosis removal with PCI. Several mechanisms can contribute to microvascular dysfunction in the post-stenotic myocardium after “successful” vessel recanalization. Distal embolization of atherosclerotic debris during the angioplasty procedure may jeopardize microvascular function [71, 72]. The development of structural microcirculatory remodeling in the myocardium subtended by the stenotic artery may cause a persistent rise in microvascular resistance after stenosis removal. The presence of preexisting diffused microvascular dysfunction, no related to the stenosis, may simply be unmasked once the stenosis has resolved. Evidence has been reported in support of these three hypotheses. Distal embolization can indeed occur during angioplasty, though it rarely causes appreciable microvascular dysfunction, unless bulky thrombi in degenerated venous grafts are dislodged and displaced in the distal vessels [73, 74]. In a study where microvascular resistances were measured before and after PCI, only patients with elevated microvascular resistances prior to PCI had abnormal microvascular resistances also after the procedure, while patients presenting with normal microvascular resistances before PCI had normal resistance also after PCI. These observations excluded, in the group of patients studied, any significant contribution of procedure-related microembolization in the abnormal post-PCI microvascular resistances [75] (Fig. 4). These observations also explain the findings of coronary flow reserve (CFR) and fractional flow reserve (FFR) during percutane-
Guarini et al.
ous interventions. Frequently, a mismatch in FFR and CFR is documented after successful PCI: stenosis removal normalize immediately FFR in all patients, including those that retain an abnormal CFR [64]. The absence of significant effects of abciximab on stenosis resistance in the studies, both under autoregulation and at maximal vasodilatation, suggests that the drug does not influence stenotic hemodynamics. An alternative explanation for the clinical benefits of antiplatelet agents in acute coronary syndromes could be sought at the level of the microcirculation. Platelets may be activated by exposure to thrombus, injured endothelium, and collagen while crossing the stenotic segment [68, 76-78]. These activated platelets can increase microvascular resistances as a result of micro embolization and/or release of constrictive, pro-adhesive, and proinflammatory factors [79, 80]. The additive effect of abciximab on top of a large dose of adenosine suggests the prevention of microvascular obstruction, leading to an increase in the vascular bed reached by perfusion, both at baseline and during maximal vasodilatation. In other studies performed in patients with stenosis in only one coronary vessel, microvascular dysfunction has been documented in both the post-stenotic myocardium and in the myocardium perfused by non-stenotic vessels, suggesting that microvascular dysfunction may exist independently from the stenosis. This substrate of generalized microvascular dysfunction may precipitate and aggravate ischaemia when a stenosis develops, and would persist after its removal with PCI [65, 67] (Fig. 5) 3. Effect of Stenosis on Vascular Response to Vasoactive Substances Downstream from a coronary stenosis, the vascular response to vasoactive substances may be altered. Serotonin, which exerts a powerful vasodilation effect in normal coronary vessels, may elicit a vasoconstrictive response in poststenotic vascular networks [81, 82]. Endothelial dysfunction associated with coronary atherosclerosis changes the vascular response to acetylcholine from vasodilatation to vasoconstriction [83]. Indeed, studies have documented that an alteration of the synergistic role of endothelin and nitric oxide may elicits coronary microvascular constriction during ischemia [84].
Fig. (4). Changes in microvascular resistance before and after PCI in patients with normal or abnormal CFR after coronary revascularization. Only patients with normal microvascular resistance (distal pressure/blood flow during hyperemia) before PCI, exhibited normal CFR after revascularization. Those patients with elevated microvascular resistance and abnormal CFR after PCI exhibited also increased microvascular resistance prior to PCI. These data suggests a preexisting microcirculatory dysfunction that was not affected by revascularization. Modified from Marzilli [57]
Microvascular Function/Dysfunction Downstream a Coronary Stenosis
Fig. (5). Relative blood flow measurement in patients with single coronary artery disease in the stenotic vessel (white), and in the non-stenotic vessel of the same patient (grey). Data are compared to control (patients with no CAD), under baseline, pacing, and dypiridamole. Even in the non- stenotic vessel (black) blood flow value were lower than the control, suggesting a diffuse impairment of the coronary microcirculation. Modified from Sambuceti 1994 [63]
In addition platelets, activated by exposure to damaged endothelium, may produce vasoactive substances that contribute to elevated microvascular resistance. Inhibition of platelet aggregation may substantially reduce coronary microvascular resistance [57]. 4. Effect of Stenosis on Perfused Volume Available technologies allow the contemporary assessment of coronary blood flow and perfused myocardial volume. An experimental setting coupling both measurements allow to estimate the interrelationship between coronary pressure, blood flow, and myocardial volume. Dorge and co-workers reported striking differences in flow-function relationships caused by stenosis or microvascular embolization (mimicking microvascular dysfunction) [85]. Acutely, coronary stenosis or microvascular obstruction had the same effect on cardiac function, with similar acute flow-function relationship. However, function progressively deteriorated over time in the embolization group versus improvement in function in the stenosis one. The authors have proposed that micro areas of ischemia may elicit inflammation and causes expression of cytokines leading to the deterioration of function. This paper, with some previous studies have critical questioned the hypothesis that flow-function relationships is linear or curvilinear. In line with this concept, Sambuceti and colleageus [86] reported the observation that perfusion pressure directly modifies the total perfusion area of an artery being studied. The impact of this observation focuses on whether following an intervention, such as PCI, after which coronary perfusion pressure downstream the remodeled lesion increases, the resulting increase in flow is due to enhanced myocardial perfusion per unit mass or it is due to an increase in the perfusion territory? Spyrou and colleagues [87] made an equally important observation that affects interpretations of flow responses following cardiac revascularization. Specifically, these investigators found that coronary flow reserve increases progressively over the time after angioplasty; this implies remodeling in the downstream microcirculation associated with the increase in the perfusion pressure. It is conceivable that by reducing effective coronary perfusion pressure, a severe coronary stenosis reduces the volume of perfused myocardium. Stenosis removal by angioplasty and stenting increases distal coronary pressure and perfused volume [88]. These increases in driving pressure and perfused volume appear to be linearly related. These findings suggest that in the presence of a severe stenosis observed resting blood flow is distributed only to a portion of the vascular units. This would be in agreement with the hypothesis that chronic under perfusion in myocardial regions is partly a result of active microcirculatory vasoconstriction, triggered by a reduced post-stenotic driving pressure.
Current Pharmaceutical Design, 2013, Vol. 19, No. 00
7
CONCLUSIONS The presence of a tight coronary stenosis is associated with functional and structural changes in the dependent microcirculation. This markedly modifies microvascular behavior both under resting conditions and during physical or pharmacological stimulation. Contrary to predictions from animal models, increases in myocardial oxygen demands are associated with active vasoconstriction in the coronary microcirculation downstream from a severe stenosis. This phenomenon contributes to precipitate ischaemia in stable coronary artery disease and in acute coronary syndromes. Although this paradoxical behavior is promptly reverted by stenosis removal, minimal microvascular resistances may remain markedly elevated after stenosis removal and impair coronary blood flow reserve in the long term. All together these data suggest that beyond the well-established role of coronary atherosclerotic plaque, microvascular abnormalities should be considered in the pathogenesis of myocardial ischemia. Coronary atherosclerosis is just an epiphenomenon of a more deep pathological process that impair at several level the ability of the coronary circulation to finely regulate coronary blood flow. In order to successfully treat patients with ischemic heart disease, Gould’s dogma should be overcome in favor of an integrated approach to the coronary circulation. This critical approach to ischemic heart disease should not be limited to a mere translation of animal data to humans, but taking into account the complexity of the phenomenon and patients comorbidities. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1]
[2]
[3] [4]
[5] [6] [7] [8] [9]
[10] [11]
[12]
Gould KL, Lipscomb K, Calvert C. Compensatory changes of the distal coronary vascular bed during progressive coronary constriction. Circulation 1975; 51(6): 1085-94. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974; 33(1): 87-94. Kuo L, Davis MJ, Chilian WM. Endothelium-dependent, flowinduced dilation of isolated coronary arterioles. Am J Physiol 1990; 259(4 Pt 2): H1063-70. Picchi A, Limbruno U, Focardi M, et al. Increased basal coronary blood flow as a cause of reduced coronary flow reserve in diabetic patients. Am J Physiol Heart Circ Physiol.; 301(6): H2279-84. Picchi A, Capobianco S, Qiu T, et al. Coronary microvascular dysfunction in diabetes mellitus: A review. World J Cardiol. 26; 2(11): 377-90. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007; 356(8): 830-40. Feigl EO. Coronary physiology. Physiol Rev 1983; 63(1): 1-205. Chilian WM. Microvascular pressures and resistances in the left ventricular subepicardium and subendocardium. Circ Res 1991; 69(3): 561-70. Chilian WM, Eastham CL, Marcus ML. Microvascular distribution of coronary vascular resistance in beating left ventricle. Am J Physiol 1986; 251(4 Pt 2): H779-88. Jones CJ, Kuo L, Davis MJ, et al. Regulation of coronary blood flow: coordination of heterogeneous control mechanisms in vascular microdomains. Cardiovasc Res 1995; 29(5): 585-96. Deussen A, Ohanyan V, Jannasch A, et al. Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol.; 52(4): 794-801. Tune JD, Gorman MW, Feigl EO. Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol 2004; 97(1): 404-15.
8 Current Pharmaceutical Design, 2013, Vol. 19, No. 00 [13]
[14]
[15] [16]
[17] [18]
[19]
[20] [21]
[22]
[23]
[24]
[25]
[26] [27]
[28] [29]
[30] [31] [32]
[33]
[34] [35]
Saitoh S, Kiyooka T, Rocic P, et al. Redox-dependent coronary metabolic dilation. Am J Physiol Heart Circ Physiol 2007; 293(6): H3720-5. Yada T, Shimokawa H, Hiramatsu O, et al. Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo. Circulation 2003; 107(7): 1040-5. Koller A, Bagi Z. Nitric oxide and H2O2 contribute to reactive dilation of isolated coronary arterioles. Am J Physiol Heart Circ Physiol 2004; 287(6): H2461-7. Headrick J, Willis RJ. Contribution of adenosine to changes in coronary flow in metabolically stimulated rat heart. Can J Physiol Pharmacol 1988; 66(2): 171-3. Duncker DJ, van Zon NS, Pavek TJ, et al. Endogenous adenosine mediates coronary vasodilation during exercise after K(ATP)+ channel blockade. J Clin Invest 1995; 95(1): 285-95. Ishibashi Y, Duncker DJ, Zhang J, et al. ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ Res 1998; 82(3): 346-59. Lavallee M, Takamura M, Parent R, et al. Crosstalk between endothelin and nitric oxide in the control of vascular tone. Heart Fail Rev 2001; 6(4): 265-76. Hecker M, Fleming I, Busse R. Kinin-mediated activation of endothelial no formation: possible role during myocardial ischemia. Agents Actions Suppl 1995; 45: 119-27. Sato A, Sakuma I, Gutterman DD. Mechanism of dilation to reactive oxygen species in human coronary arterioles. Am J Physiol Heart Circ Physiol 2003; 285(6): H2345-54. Rogers PA, Dick GM, Knudson JD, et al. H2O2-induced redoxsensitive coronary vasodilation is mediated by 4-aminopyridinesensitive K+ channels. Am J Physiol Heart Circ Physiol 2006; 291(5): H2473-82. Kokusho Y, Komaru T, Takeda S, et al. Hydrogen peroxide derived from beating heart mediates coronary microvascular dilation during tachycardia. Arterioscler Thromb Vasc Biol 2007; 27(5): 1057-63. Kanatsuka H, Sekiguchi N, Sato K, et al. Microvascular sites and mechanisms responsible for reactive hyperemia in the coronary circulation of the beating canine heart. Circ Res 1992; 71(4): 91222. Kanatsuka H, Lamping KG, Eastham CL, et al. Heterogeneous changes in epimyocardial microvascular size during graded coronary stenosis. Evidence of the microvascular site for autoregulation. Circ Res 1990; 66(2): 389-96. DeFily DV, Chilian WM. Coronary microcirculation: autoregulation and metabolic control. Basic Res Cardiol 1995; 90(2): 112-8. Chilian WM, Layne SM. Coronary microvascular responses to reductions in perfusion pressure. Evidence for persistent arteriolar vasomotor tone during coronary hypoperfusion. Circ Res 1990; 66(5): 1227-38. Kuo L, Davis MJ, Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol 1988; 255(6 Pt 2): H1558-62. Boatwright RB, Downey HF, Bashour FA, et al. Transmural variation in autoregulation of coronary blood flow in hyperperfused canine myocardium. Circ Res 1980; 47(4): 599-609. Miller FJ, Jr., Dellsperger KC, Gutterman DD. Myogenic constriction of human coronary arterioles. Am J Physiol 1997; 273(1 Pt 2): H257-64. Nowicki PT, Flavahan S, Hassanain H, et al. Redox signaling of the arteriolar myogenic response. Circ Res 2001; 89(2): 114-6. Meininger GA, Davis MJ. Cellular mechanisms involved in the vascular myogenic response. Am J Physiol 1992; 263(3 Pt 2): H647-59. Folgering JH, Sharif-Naeini R, Dedman A, et al. Molecular basis of the mammalian pressure-sensitive ion channels: focus on vascular mechanotransduction. Prog Biophys Mol Biol 2008; 97(2-3): 18095. Earley S, Waldron BJ, Brayden JE. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 2004; 95(9): 922-9. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 2002; 82(1): 131-85.
Guarini et al. [36]
[37] [38]
[39] [40] [41]
[42] [43]
[44]
[45] [46]
[47] [48]
[49]
[50] [51]
[52]
[53]
[54]
[55]
[56]
[57]
Slish DF, Welsh DG, Brayden JE. Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone. Am J Physiol Heart Circ Physiol 2002; 283(6): H2196-201. Khan TA, Bianchi C, Ruel M, et al. Mitogen-activated protein kinase inhibition and cardioplegia-cardiopulmonary bypass reduce coronary myogenic tone. Circulation 2003; 108 Suppl 1: II348-53. Wang SY, Friedman M, Franklin A, et al. Myogenic reactivity of coronary resistance arteries after cardiopulmonary bypass and hyperkalemic cardioplegia. Circulation 1995; 92(6): 1590-6. Recchia FA, Senzaki H, Saeki A, et al. Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine. Circ Res 1996; 79(4): 849-56. Ueeda M, Silvia SK, Olsson RA. Nitric oxide modulates coronary autoregulation in the guinea pig. Circ Res 1992; 70(6): 1296-303. Kuo L, Chilian WM, Davis MJ. Interaction of pressure- and flowinduced responses in porcine coronary resistance vessels. Am J Physiol 1991; 261(6 Pt 2): H1706-15. Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995; 91(5): 1314-9. Miura H, Wachtel RE, Liu Y, et al. Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels. Circulation 2001; 103(15): 1992-8. Miura H, Liu Y, Gutterman DD. Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+-activated K+ channels. Circulation 1999; 99(24): 3132-8. Sato A, Miura H, Liu Y, et al. Effect of gender on endotheliumdependent dilation to bradykinin in human adipose microvessels. Am J Physiol Heart Circ Physiol 2002; 283(3): H845-52. Beyar R, Sideman S. Time-dependent coronary blood flow distribution in left ventricular wall. Am J Physiol 1987; 252(2 Pt 2): H417-33. Hoffman JI. Transmural myocardial perfusion. Prog Cardiovasc Dis 1987; 29(6): 429-64. Stein PD, Sabbah HN, Marzilli M, et al. Comparison of the distribution of intramyocardial pressure across the canine left ventricular wall in the beating heart during diastole and in the arrested heart. Evidence of epicardial muscle tone during diastole. Circ Res 1980; 47(2): 258-67. Marzilli M, Goldstein S, Sabbah HN, et al. Modulating effect of regional myocardial performance on local myocardial perfusion in the dog. Circ Res 1979; 45(5): 634-41. Buckberg GD, Fixler DE, Archie JP, et al. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res 1972; 30(1): 67-81. Olivotto I, Girolami F, Sciagra R, et al. Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. J Am Coll Cardiol. 16; 58(8): 839-48. Olivotto I, Cecchi F, Gistri R, et al. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol 2006; 47(5): 1043-8. Cecchi F, Olivotto I, Gistri R, et al. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003; 349(11): 1027-35. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent STsegment elevation: the Task Force on the Management of STSegment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29(23): 2909-45. Zhao XQ, Theroux P, Snapinn SM, et al. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation 1999; 100(15): 1609-15. Gurbel PA, Galbut B, Bliden KP, et al. Effect of eptifibatide for acute coronary syndromes: rapid versus late administration-therapeutic yield on platelets (The EARLY Platelet Substudy). J Thromb Thrombolysis 2002; 14(3): 213-9. Marzilli M, Sambuceti G, Testa R, et al. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol 2002; 40(12): 2102-9.
Microvascular Function/Dysfunction Downstream a Coronary Stenosis [58]
[59] [60]
[61] [62] [63]
[64]
[65]
[66]
[67] [68]
[69] [70]
[71]
[72]
[73] [74]
Lipscomb K, Gould KL. Mechanism of the effect of coronary artery stenosis on coronary flow in the dog. Am Heart J. Jan 1975; 89(1): 60-7. Hoffman JI, Buckberg GD. Pathophysiology of subendocardial ischaemia. Br Med J 1975; 1(5949): 76-9. Sambuceti G, Marzilli M, Fedele S, et al. Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease : reversal by angioplasty. Circulation 2001; 103(19): 2352-60. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation.; 124(13): 1414-25. Pepine CJ. Provoked coronary spasm and acute coronary syndromes. J Am Coll Cardiol 2008; 52(7): 528-30. Sambuceti G, Marzullo P, Giorgetti A, et al. Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease. Circulation 1994; 90(4): 1696-705. Sambuceti G, Marzilli M, Marraccini P, et al. Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease. Circulation 1997; 95(12): 2652-9. Marzilli M, Sambuceti G, Fedele S, et al. Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina. J Am Coll Cardiol 2000; 35(2): 327-34. Sambuceti G, Marzilli M, Mari A, et al. Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium. Am J Physiol Heart Circ Physiol 2005; 288(5): H2298-305. Wilson RF, Laxson DD, Lesser JR, et al. Intense microvascular constriction after angioplasty of acute thrombotic coronary arterial lesions. Lancet 1989; 1(8642): 807-11. Uren NG, Crake T, Lefroy DC, et al. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J Am Coll Cardiol 1993; 21(3): 612-21. Uren NG, Crake T, Lefroy DC, et al. Altered resistive vessel function after coronary angioplasty is not due to reduced production of nitric oxide. Cardiovasc Res 1996; 32(6): 1108-14. Dupouy P, Aptecar E, Pelle G, et al. Early changes in coronary flow physiology after balloon angioplasty or stenting: a 24-hour Doppler flow velocity study. Catheter Cardiovasc Interv 2002; 57(2): 191-8. Cuisset T, Hamilos M, Melikian N, et al. Direct stenting for stable angina pectoris is associated with reduced periprocedural microcirculatory injury compared with stenting after pre-dilation. J Am Coll Cardiol 2008; 51(11): 1060-5. Marzilli M, Mariani M. Ischemia-reperfusion and microvascular dysfunction: implications for salvage of jeopardized myocardium and reduction of infarct size. Ital Heart J 2001; 2 Suppl 3: 40S-2. Marzilli M, Orsini E, Marraccini P, et al. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation 2000; 101(18): 2154-9. Minamino T, Kitakaze M, Asanuma H, et al. Endogenous adenosine inhibits P-selectin-dependent formation of coronary
Received: October 11, 2012
Accepted: November 16, 2012
Current Pharmaceutical Design, 2013, Vol. 19, No. 00
[75]
[76]
[77]
[78] [79]
[80]
[81] [82]
[83]
[84]
[85]
[86]
[87] [88]
9
thromboemboli during hypoperfusion in dogs. J Clin Invest 1998; 101(8): 1643-53. Leppaluoto J, Ruskoaho H. Endothelin peptides: biological activities, cellular signalling and clinical significance. Ann Med 1992; 24(3): 153-61. Zeiher AM, Krause T, Schachinger V, et al. Impaired endotheliumdependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 1995; 91(9): 2345-52. Koch KC, vom Dahl J, Kleinhans E, et al. Influence of a platelet GPIIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy. J Am Coll Cardiol 1999; 33(4): 998-1004. Gorman MW, Sparks HV, Jr. Progressive coronary vasoconstriction during relative ischemia in canine myocardium. Circ Res 1982; 51(4): 411-20. Hori M, Inoue M, Kitakaze M, et al. Role of adenosine in hyperemic response of coronary blood flow in microembolization. Am J Physiol 1986; 250(3 Pt 2): H509-18. Golino P, Piscione F, Willerson JT, et al. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med 1991; 324(10): 641-8. Sambuceti G, L'Abbate A, Marzilli M. Why should we study the coronary microcirculation? Am J Physiol Heart Circ Physiol 2000; 279(6): H2581-4. Quyyumi AA, Dakak N, Mulcahy D, et al. Nitric oxide activity in the atherosclerotic human coronary circulation. J Am Coll Cardiol 1997; 29(2): 308-17. Taylor AJ, Al-Saadi N, Abdel-Aty H, et al. Elective percutaneous coronary intervention immediately impairs resting microvascular perfusion assessed by cardiac magnetic resonance imaging. Am Heart J 2006; 151(4): 891 e891-7. Kusmic C, Lazzerini G, Coceani F, et al. Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin. Am J Physiol Heart Circ Physiol 2006; 291(4): H1814-21. Dorge H, Neumann T, Behrends M, et al. Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol 2000; 279(6): H2587-92. Sambuceti G, Marzilli M, Mari A, et al. Clinical evidence for myocardial derecruitment downstream from severe stenosis: pressure-flow control interaction. Am J Physiol Heart Circ Physiol 2000; 279(6): H2641-8. Spyrou N, Khan MA, Rosen SD, et al. Persistent but reversible coronary microvascular dysfunction after bypass grafting. Am J Physiol Heart Circ Physiol 2000; 279(6): H2634-40. Selvanayagam JB, Cheng AS, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention: a quantitative magnetic resonance perfusion study. Circulation 2007; 116(13): 1458-64.
